Trans-{4-[(alkylamino)methyl]cyclohexyl}acetic acid esters are useful as reagents or raw material compounds for manufacture of medicaments, agricultural chemicals, and industrial products. For example, in each of the following publications (Patent documents 1 to 6), trans-{4-[(alkylamino)methyl]cyclohexyl}-acetic acid esters are described as important raw material compounds for preparation of: trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-5-methyl-4-(trifluoromethyl)phenyl](ethyl)amino}-methyl)cyclohexyl]acetic acid hydrochloride represented by the following formula (A) (Patent document 1, Example 142), trans-[4-({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid represented by the following formula (B) (Patent document 2, Ex. 73), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](5-morpholinopyrimidin-2-yl)amino}methyl)-4-(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid represented by the following formula (C) (Patent document 3, Ex. 57), trans-[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-5-(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetic acid represented by the following formula (D) (Patent document 4, Ex. 14), trans-[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)quinolin-2-yl](ethyl)amino}methyl)cyclohexyl]acetic acid represented by the following formula (E) (Patent document 5, Ex. 4), trans-(4-{[{2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino]methyl}cyclohexyl)acetic acid represented by the following formula (F) (Patent document 6, Example 45) and the like, which are pyrimidine compounds having a dibenzylamine structure having a cholesterol ester transfer protein (CETP) inhibitory activity and are useful as prophylactic and/or therapeutic agents for hyperlipidemia, arteriosclerosis, heart diseases and the like.

As a method for preparing a trans-{4-[(ethylamino)methyl]cyclohexyl}acetic acid ester, the method shown in the following reaction scheme is known. This method uses 4-oxocyclohexanecarboxylic acid ethyl ester as a starting material, and comprises the steps of derivatizing the starting material to obtain the cyclohexylacetic acid compound by a carbon increasing reaction based on the Horner-Wittig-Emmons reaction, reducing the double bond of the unsaturated ester of the cyclohexylacetic acid compound to obtain the cyclohexylcarboxylic acid compound as a mixture of the compounds of cis- and trans-configurations, then converting the resulting cyclohexylcarboxylic acid into the acid chloride without separating the isomers, and then converting the acid chloride into the amide compound by a reaction with ethylamine. The desired amide compound having the trans-configuration can be separated by repeating recrystallization several times. The resulting amide compound can be reduced with sodium borohydride in the presence of acetic acid to obtain a trans-{4-[(ethylamino)methyl]cyclohexyl}acetic acid ester, which is an amine compound (refer to Patent document 1, Example 169).
Reaction Route 1

However, the operations of the aforementioned method are complicated, since the desired amide intermediate having the trans-configuration is separated and purified from a mixture of the cis- and trans-isomers by recrystallization, and thus the total yield is also low (32.2%). Further, it is difficult to carry out the conversion of the non-desired cis-compound into the trans-compound by an ordinary method, and therefore, the method also suffers from a problem that the cis-compound cannot be recycled. Furthermore, the 4-oxocyclohexanecarboxylic acid ethyl ester as the starting material is not inexpensive at present, and therefore the method cannot be regarded as an industrially efficient and advantageous preparation method.
In order to avoid loss in a yield due to the separation by recrystallization, a method has been proposed in which the cyclohexylacetic acid, obtained by the carbon increasing reaction based on the Horner-Wittig-Emmons reaction and the successive reduction, is derived into a benzyl ester intermediate so as to facilitate the separation of the cis- and trans-isomers. After separation and purification of the mixture of the isomers is carried out by column chromatography to obtain the cyclohexylacetic acid derivative of the trans-configuration, the target compound can be obtained by steps similar to those of the aforementioned method (see, Intermediate 7 and Intermediate 13 of Patent document 2). This reaction route is shown with reaction formulas as follows.
Reaction Route 2

However, this method additionally comprises the steps of converting the carboxylic acid into the benzyl ester intermediate for the separation by column chromatography and, after separating the desired objective substance, converting the benzyl ester into a carboxylic acid by hydrogenolysis. Therefore, an yield may possibly be reduced significantly due to the separation of the isomers. Further, the operations of the column chromatography for the separation of the isomers are complicated, and accordingly, the method is considered not to be efficient preparation method from an industrial viewpoint.